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Ipilimumab Plus Sargramostim Vs Ipilimumab Alone

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Ipilimumab Plus Sargramostim Vs Ipilimumab Alone E1608 Revised 4/11, Addendum #3 Eastern Cooperative Oncology Group A Phase II Trial of GM-CSF Protein Plus Ipilimumab in Patients with Advanced Melanoma STUDY CHAIR: F. Stephen Hodi, M.D. STUDY CO-CHAIR: David McDermott, M.D. STUDY STATISTICIAN: Sandra Lee, Sc.D. PATHOLOGY CO-CHAIR: Uma Rao, M.D. MELANOMA COMMITTEE CHAIR: John Kirkwood, M.D. Rev. 4/11 COMMUNITY CO-CHAIR: Gary Cohen, M.D. Version Date: February 24, 2012 STUDY PARTICIPANTS ACTIVATION DATE ECOG US Sites Only December 28, 2010 CALGB Dana-Farber Cancer Institute Only PRE-ACTIVATION DATE November 1, 2010 Addendum #1 – Incorporated Prior to Activation Addendum #2 – 12/10 Addendum #3 – 4/11 Addendum #4 – 10/11 Addendum #5 – 4/12 Agents IND # NSC # Supply Ipilimumab 10200 NSC 732442 NCI-Supplied GM-CSF NSC 613795 Industry Supplied Downloaded From: https://jamanetwork.com/ on 09/29/2021 Eastern Cooperative E1608 Oncology Group Revised 4/12, Addendum #5 Table of Contents Schema..............................................................................................................................i 1. Introduction ...............................................................................................................1 2. Objectives ...............................................................................................................11 3. Selection of Patients ...............................................................................................12 4. Registration and Randomization Procedures .........................................................15 5. Treatment Plan........................................................................................................18 6. Measurement of Effect............................................................................................33 7. Study Parameters ...................................................................................................44 8. Drug Formulation and Procurement........................................................................47 9. Statistical Considerations........................................................................................55 10. Pathology Review ...................................................................................................57 11. Correlative Studies..................................................................................................59 12. Records to Be Kept.................................................................................................62 13. Patient Consent and Peer Judgment......................................................................62 14. References..............................................................................................................62 Appendix I Informed Consent Template for Cancer Treatment Trials (English Language).........................................................................................................................1 Appendix II Pathology Submission Guidelines .................................................................1 Appendix III Patient Thank You Letter.............................................................................1 Appendix IV Suggested Work-up and Treatment for IMMUNE-Related Adverse EVENTS (IRAEs) ..............................................................................................................1 Appendix V Recommended Diarrhea Management Algorithm........................................1 Appendix VI Recommended Hepatotoxicity Management Algorithm..............................1 Appendix VII Recommended Endocrinopathy Management Algorithm ..........................1 Appendix VIII Shipping Kit Request Facsimile Form ........................................................1 Appendix IX Specimen Shipment/Requisition Form.........................................................1 Appendix X Medication Diary............................................................................................1 Appendix XI E1608 Cooperative Research and Development Agreement (CRADA)......1 Appendix XII E1608 GM-CSF Drug Request Form ..........................................................1 Appendix XIII Certificate of Destruction of Clinical Trial Drugs ........................................1 Appendix XIV Self-Administration Guide for GM-CSF......................................................1 Rev. 4/12 Appendix XV Pre-Existing Autoimmune Diseases ...........................................................1 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Eastern Cooperative E1608 Oncology Group STUDY CHAIR F. Stephen Hodi, M.D. Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Tel: (617) 632-5053 Fax: (617) 582-7992 Email: [email protected] STUDY CHAIR LIAISON (SCL) Angie Tsiaras Dana-Farber Cancer Institute 44 Binney Street Boston, MA 02115 Tel: (617) 632-6460 Email: [email protected] STUDY CO-CHAIR: David McDermott, M.D. Beth Israel Deaconess Medical Center 330 Brookline Avenue, KS-158 Boston, MA 02215 Tel: (617) 667-9920 Fax: (617) 667-9922 Email: [email protected] Downloaded From: https://jamanetwork.com/ on 09/29/2021 Eastern Cooperative E1608 Oncology Group Revised 4/11, Addendum #3 Schema i Downloaded From: https://jamanetwork.com/ on 09/29/2021 Eastern Cooperative E1608 Oncology Group 1. Introduction 1.1 Research Hypothesis The combination of CTLA-4 antibody blockade and GM-CSF secreting tumor cell vaccines demonstrates therapeutic synergies in multiple pre-clinical models (1). While CTLA-4 antibody blockade alone elicits minimal effects against poorly immunogenic tumors, concurrent vaccination with irradiated, GM-CSF secreting tumor cells is highly efficacious in the B16 melanoma, SM1 breast carcinoma, and TRAMP prostate carcinoma models. Cytotoxic T cells are critical for tumor destruction, but the augmented anti-cancer response may be associated with the loss of tolerance to normal differentiation antigens, culminating in autoimmune vitiligo (for melanoma) or prostatitis (for prostatic carcinoma). We have generated preliminary clinical data raising the possibility of important therapeutic interactions between CTLA-4 antibody blockade and GM-CSF secreting tumor cell vaccines in patients. We initially administered a single dose of ipilimumab (3 mg/kg) to 7 previously vaccinated metastatic melanoma patients (2,3). While autoimmune toxicities were mild, ipilimumab stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in 3 of 3 metastatic melanoma patients previously vaccinated with irradiated, autologous GM-CSF secreting tumor cells, whereas ipilimumab did not elicit tumor necrosis in 4 of 4 metastatic melanoma patients previously immunized with defined melanosomal antigens. Pathologic analysis of the responding metastases resected following antibody infusion demonstrated CD4+ and CD8+ T cells, CD20+ B cells producing immunoglobulin, and granulocytes juxtaposed to dying melanoma cells; moreover, a striking circumferential lymphoid infiltrate was detected in occluded tumor blood vessels, resulting in extensive ischemic necrosis. To explore the interactions of CTLA-4 blockade and GM-CSF secreting tumor cells in more detail, we treated an additional 11 melanoma patients (2,3). In these studies, repetitive doses of ipilimumab (3 mg/kg) could be administered at two month intervals, beginning one month following the completion of vaccination. In this cohort, one complete response, two partial responses, and five prolonged stable disease were observed, all ongoing with a range of follow-up from 6 to 29 months. No patient manifested grade III or IV toxicity, although mild rashes and constitutional symptoms were noted. Consistent with pre-clinical studies indicating that CTLA-4 blockade stimulates Treg proliferation, we found CD4+FoxP3 expressing cells in the cutaneous inflammatory reactions and tumor metastases. To examine whether these principles were operative in other tumor types, we administered ipilimumab to 10 advanced ovarian carcinoma patients who were previously immunized with irradiated, autologous GM-CSF secreting tumor cells (2,3). In this cohort, 5 patients manifested a lupus-like rash and 2 showed inflammatory gastritis/colitis. Five patients displayed a reduction or stabilization of CA-125 levels (including one with a dramatic radiographic response) and one patient with normal CA-125 level showed extensive hemorrhagic tumor necrosis by pathologic analysis. ASCO presentations combining GM-CSF with CTLA-4 blockade in hormone refractory prostate cancer have demonstrated clinical responses, with > 50% experiencing declines in PSA. Correlative sciences demonstrated the expansion of both activated effector and regulatory cells in this patient population (4,5). Together, these findings suggest that more detailed analysis of the interplay of GM-CSF and CTLA-4 antibody blockade should be undertaken. One key issue with significant practical implications is whether the systemic administration of GM-CSF protein might synergize effectively with CTLA-4 blockade. In this context, the injection of recombinant GM-CSF protein can enhance dendritic cell activation and thereby potentiate anti-tumor T and B cell responses. The cytokine mediates anti-tumor effects in some patients with advanced prostate or ovarian carcinoma and is currently being evaluated as a vaccine adjuvant in Phase III trials in melanoma and lymphoma. 1 Downloaded From: https://jamanetwork.com/ on 09/29/2021 Eastern Cooperative E1608 Oncology Group There are increasing
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